# APPENDIX N

Integrated Risk Information System Background Paper



# WATERQUALITY STANDARDS HANDBOOK

SECONDEDITION

# IRIS

BACKGROUND 

# PAPER

Integrated Risk Information System
Office of Health and Environmental Assessment

Environmental Assessment
Office of Research and Development

FEBRUARY, 1993 VERSION 1.0

# IRIS Background Paper

On February 25, 1993, a FEDERAL REGISTER notice (58 FR 11490) was published on the Integrated Risk Information System (IRIS). This background paper is acompanion piece to that notice.



### Table of Contents
lntroduction

............................... 1 General Background

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Data Base Contents

................................. 3 Noncancer Health Effects Information

............... 3 Cancer Effects Health Information

.................. 4 Scientific Contacts

............................. 4 Bibliographies

................................ 5 Supplementary Information

....................... 5 Use and Development of Health Hazard Information

. . . . . . . . . . 5 Management

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Oversight

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Information Development Process

....................... 6 CRAVE

..................................... 6 RfD/RfC

.................................... 8 Methods and Guidelines

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Public Involvement

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Forfurther information on IRIS, please contact:



### IRIS User Support (Operated by Computer Sciences Corporation) 26W. Martin Luther King Drive (MS-190)

Cincinnati, OH45268 Telephone (513) 569-7254 Facsimile (513) 569-7916Introduction

This background paper provides the history, purposes, and goals ofthe Integrated Risk Information System (IRIS)and adetailed description ofthe current processes used by the two Agency scientific work groups responsible for developing the health hazard information in IRIS. This background will help interested persons to better understand the focus and contents ofthe companion FEDERAL REGISTER notice.The February 25, 1993 FEDERAL REGISTER notice (58 FR 11490): (1) announces the availability ofthis paper that describes IRIS, its contents, and the current processes used bythe two Agency work groups responsible for developing IRIS information; (2)discusses anAgency activity to review IRIS processes and solicits comments on this review; (3) highlights points inthe current process where public input, including information submissions, isencouraged; (4)describes how to access IRIS; and (5)announces a new process to publish regularly a list ofthe substances scheduled for IRISwork group review and to solicit pertinent data, studies, and comments on these substances.



### General Background
IRIS isan EPAdata base, updated monthly, containing Agency consensus positions on the potential adverse human health effects of approximately 500 specific substances. Itcontains summaries of EPAqualitative and quantitative human health information that support two ofthe four major steps ofthe risk assessment process outlined inthe National Research Council’s (NRC) 1983 publication, “RiskAssessment in the Federal Government: Managing the Process.”
The risk assessment process described inthe 1983 NRC publication consists of four major steps: hazard identification, dose-response evaluation, exposure assessment, and risk characterization. IRISincludes information in support ofthe first two ofthose steps, hazard identification and dose-response evaluation. Hazard identification isthe qualitative determination of how likely it isthat asubstance will increase the incidence and/or severity of an adverse health effect. Dose-response evaluation isthe quantitative relationship between the magnitude ofthe effect and the dose inducing such an effect. IRIS information supporting risk characterization consists of brief statements on the quality of data and very general statements on confidence inthe dose-response evaluation. IRISconsensus information does not include exposure assessment information. Combined with specific situational exposure assessment information, the summary health hazard information in IRIS may be used as one source in evaluating potential public health risks of or from environmental contaminants.Many EPA program offices and program support offices, including the Office

of Research and Development, both at Headquarters and in EPA’s ten Regional offices, are involved in assessment activities in support ofvarious legislative mandates. Inthe 1980s as health risk assessment became a more widespread practice across Agency programs, the need became clear for greater consensus and consistency in the areas of hazard identification and dose-response assessment. Itwas determined that an internal process should be established for reaching anAgency-wide judgment on the potential health effects of substances of common interest to these offices, and asystem developed for communicating that Agency judgment to EPA risk assessors and risk managers. These would provide the needed consistency and coordination. In 1986,two EPAwork groups with representation from program offices involved in risk assessment were convened to carry out such an internal process to reach consensus Agency positions on achemical-by-chemical basis. In 19*6, the IRISdata base was created for EPAstaff asthe official repository ofthat consensus information. OnJune 2, 1988, a FEDERAL REGISTER notice (53 FR20162-20164) of public availability of IRISwas published. That notice described IRIS,the types of risk information itcontains, and how to get access to the system. It informed the public about the establishment ofthe IRIS Information Submission Desk. The submission desk was intended to provide opportunity for public input. The notice explained the procedures for submission of data or comments by interested parties on substances either on IRISor scheduled for review by the work groups. As stated inthe June 1988 notice, a list ofthe substances scheduled for work group review has been aseparate file on IRISsince it became publicly available. Itwas hoped that users would submit pertinent information to the IRIS Information Submission Desk. Infact, few users have taken advantage ofthe opportunity to submit data and comments. Therefore, data submission procedures are reiterated inthe FEDERAL REGISTER notice (56 FR 11490) related to this paper and a listof the substances scheduled for review by specific work groups is included. The data submission procedures will be reprinted inthe FEDERAL REGISTERevery 6 months with a new or revised list of substances scheduled for work group review. Forthe latest status of the substances scheduled for review, interested persons should first check the IRIS data base itself or contact: IRIS User Support (Operated by Computer Sciences Corporation) U.S. EPA 26W. Martin Luther King Drive (MS-190) Cincinnati, OH 45266 Telephone: (513) 569-7254 Facsimile: (513) 569-7916

### Data Base Contents

The core of IRISisthe three consensus health hazard information summary sections: the reference dose for noncancer health effects resulting from oral exposure, the reference concentration for noncancer health effects resulting from inhalation exposure, and the carcinogen assessment for 

### both oral and inhalation exposure. All ofthese terms are commonly used forjudging the effects of lifetime exposure to agiven substance or mixture. Citations for the scientific methodologies that arethe basis for the consensus health hazard sections on IRISare included on page 10ofthis paper. In addition, an IRISsubstance file may include supplemental information such assummaries of health advisories, regulatory actions, and physical/chemical properties. Noncancer Health Effects Information
An oral reference dose (RfD)is an estimate (with uncertainty spanning perhaps an order of magnitude) of adaily oral exposure to the human population (including sensitive subgroups) that is believed likely to be without an appreciable risk of certain deleterious effects during a lifetime (“Reference Dose [RfD]; Description and Use in Health RiskAssessment” Regulatory Toxicology and Pharmacology 8:471-486, 1988). RfDsare developed by an assessment method that assumes that there is adose threshold below which adverse effects will not occur. An RfD,which isexpressed in milligrams per kilogram per day (mg/kg-day), is based on the determination of a critical effect from a review of alltoxicity data and ajudgment ofthe necessary uncertainty and modifying factors based on a review of available data. IRISsubstance files contain the following information pertaining to the oral RfD: reference dose summary tables, principal and supporting studies, uncertainty and modifying factors used incalculating the RfD,astatement of confidence inthe RfD, EPA documentation and review, EPAscientific contacts, and complete bibliographies for references cited. The inhalation reference concentration (RfC)isanalogous to the oral RfD (Interim Methods for Development of Inhalation Concentrations, EPA/600/8-90/066A). It isalso based on the assumption that thresholds existfor noncancer toxic effects. The RfCconsiders toxic effects for both the respiratory system (portal-of-entry) and for effects peripheral to the respiratory system (extra-respiratory). The inhalation RfC is expressed in milligrams per cubic meter (mg/cu.m). The RfC method departs from that used to determine the oral RfDprimarily bythe integration ofthe anatomical and physiological dynamics ofthe respiratory system (i.e., portal-of-entry) with the physicochemical properties ofthe substance or substances entering the system. Different dosimetric adjustments are made according to whether the substance isa particle or gas and whether the observed toxicity is respiratory or extra-respiratory. These adjustments scale the concentration ofthe substance that causes an observed effect in laboratory animals (or in humans, when available from occupational epidemiology studies) to a human equivalent concentration for ambient exposures.
3IRISsubstance files contain the following inhalation RfCinformation: reference

concentration summary tables, description of dosimetric adjustment, principal and supporting studies, uncertainty and modifying factors used to calculate the RfC, a statement of confidence inthe RfC, EPAdocumentation and review, EPA scientific contacts, and complete bibliographies for references cited. Cancer Health Effects Information The carcinogen assessment of an IRISsubstance file contains health hazard identification and dose-response assessments developed from procedures outlined in the EPAGuidelines for Carcinogen RiskAssessment (51 FR33992-43003, September 24, 1986). Each cancer assessment, as a rule, is based on anAgency document that has received external peer review. The hazard identification involves ajudgment inthe form of aweight-of-evidence classification ofthe likelihood that the substance isa human carcinogen. It includes the type of data used asthe basis ofthe classification. Thisjudgment is made independently of considerations ofthe strength ofthe possible response. The dose-response assessment isaquantitative estimate ofthe potential activity or magnitude of asubstance’s carcinogenic effect, usually expressed as a cancer unit risk. A cancer unit risk isan upper-bound estimate on the increased likelihood that an individual will develop cancer when exposed to asubstance over a lifetime at aconcentration of either 1microgram per liter (1μg/L) in drinking water for oral exposure or 1microgram per cubic meter (1μg/cu.m) in airfor continuous inhalation exposure. Generally, aslope factor for dietary use isalso given. It isan upper-bound estimate of cancer riskfor humans per milligram of agent per kilogram of body weight per day. IRIScontains the following information inthe cancer assessment section: EPA weight-of-evidence classification and its basis, asummary of human carcinogenicity studies when available, asummary of animal carcinogenicity studies, asummary of other data supporting the classification, oral and/or inhalation quantitative estimates, dose-response data used to derive these estimates and the method of calculation, statements of confidence in magnitude of unit risk, documentation and review, EPA scientific contacts, and complete bibliographies for references cited. Scientific Contacts
It is important to note that ineach ofthe three sections described above, EPA staff names and telephone numbers are included as scientific contacts for further information. The Agency believes that the inclusion ofAgency scientific contacts able to discuss the basis for the Agency’s position, has been veryvaluable. These individuals play a major role in providing public access to IRISand aconduit for valued public comment.

4Bibliographies

IRIScontains full bibliographic citations for each substance file, directing the user to the primary cited studies and pertinent scientific literature. One ofthe major intents of IRISwas to encourage users to evaluate the primary literature used to develop the IRISinformation in light ofthe assumptions and uncertainties underlying the risk assessment process. Supplementary Information
In addition to the RfD, RfC,and carcinogenicity sections, IRISsubstance files may contain one or more ofthree supplementary information sections: asummary of an Office of Water’s Drinking Water Health Advisory, asummary of EPA regulatory actions, and asummary of physical/chemical properties. The only purpose ofthese supplemental sections isto serve as accessory information to the consensus health hazard information. Since the primary intent ofthe IRISdata base isto communicate EPAconsensus health hazard information, these other sections are only included as auxiliary material to provide a broader profile of asubstance and are never added until at least one ofthe consensus health hazard sections described above (namely, the RfDsection, RfCsection, or carcinogenicity section) is prepared and approved for final inclusion on the data base. These supplemental sections should not be used asthe sole or primary source of information on the current status of EPA substance-specific regulations.



### Use and Development of Health Hazard Information
The type of substance-specific consensus health hazard information on IRIS may become part ofthe supporting materials used to develop site-specific EPA health hazard assessments. These assessments may inturn lead to EPA risk management decisions, generally resulting inthe formal Agency rulemaking process. This rulemaking process often includes FEDERAL REGISTER publication of a proposed rule where the public isencouraged to comment. These comments may be directed at both the proposed rule and the scientific basis ofthe decision, including information obtained from IRISand thus offer afurther opportunity for comment on the risk information inthe context of its use. The area of human health risk assessment has evolved over the past several years. As the risk assessment community has grown and the field itself has matured, new approaches to the assessment and use of human health risk information have been developed. The evolving nature of risk assessment has also resulted in changes to IRIS. The development of methodologies such asthose for the inhalation RfC determination illustrates the ability ofthe IRISinformation development process to grow with the changing science. Areas offuture growth may include less-than-lifetime risk information and developmental toxicity risk information and other endpoint-specific health hazard information. Also, on several occasions, the information in IRIS has
5been reevaluated and modified to reflect new information and approaches. New

studies on individual substances are continually being conducted by Federal, private, and academic institutions and may have significant impact on IRIS information. In those cases, the IRISsubstance information is reevaluated in light ofthe new data; any changes resulting from that reevaluation are included on the system.


### Management of the Data Base
The IRISdata base is managed and maintained bythe Office of Health and Environmental Assessment (OHEA), Office of Research and Development (ORD). IRIS isanAgency system primarily funded by OHEA with additional significant support from EPA program offices. 

### Oversight Oversight activities for IRISare conducted bythe IRISOversight Committee, a subgroup ofthe Agency’s RiskAssessment Council. Committee membership consists of senior Agency risk assessors. The main purpose ofthe IRISOversight Committee isto serve as aforum for discussion and advice on significant scientific or science policy issues involving IRIS. The Council, which ischaired by EPA’s Deputy Administrator, receives periodic status reports on IRISand related work group activities.



### Information Development Process
There aretwo EPAwork groups, the Carcinogen RiskAssessment Verification Endeavor (CRAVE) and the Oral Reference Dose/Inhalation Reference Concentration (RfD/RfC) Work Group, that develop consensus health hazard information for IRIS. Each group consists of EPAscientists from a mix of pertinent disciplines and represents intra-Agency membership. The work groups serve asthe Agency’s final review for EPA risk assessment information. When the work groups reach consensus on the health effects information and the dose-response assessment for a particular substance, the descriptive summary isadded to IRIS. CRAVE: Information Development Procedures The goals ofthe CRAVE areto reach Agency consensus on Agency carcinogen risk assessments; to arrive at a unified view on potential cancer riskfrom exposure to specific substances across Agency programs; 

### andto identify, discuss, and resolve general issues associated with methods used to estimate carcinogenic risks for specific agents. The major outputs ofthe work group are summaries of risk



### 6information that have been previously developed and documented by scientific experts

inAgency program and program support offices, and results of discussions of general issues in carcinogen risk assessment. Scientists are selected by executive appointment from respective member offices. Membership isopen to all major Agency program and regional offices, ORD, and the Office of Policy, Planning, and Evaluation (OPPE). Substances are discussed atthe request of Agency offices or regions according to an established timetable. The CRAVE priorities are determined by the member offices. The office requesting review prepares asummary describing both ajudgment on the weight-of-evidence for potential health hazard effects and any dose-response information for the substances according to an established format. Literature files on the substances including critical studies, pertinent EPAdocuments, and other relevant supporting documentation are made available to work group members inadvance ofthe meeting. Generally, the judgment and the dose-response assessment are expected to have appeared in a publicly available document of some sort. The CRAVE usually meets bimonthly for two days. Work group members normally receive draft summaries for pre-meeting review at least one week prior to the scheduled meeting. Atthe meeting, data and documentation are examined, and there isdiscussion ofthe basis for the risk information and the methods by which itwas derived. In addition, the nature and extent of previous internal and external peer review, including the comments received, are reviewed by the work group. The summary is revised by the office originating the review to reflect the meeting discussion and accurately express the consensus view ofthe work group. After the process of revision iscompleted, the summary iscirculated again to the work group for final approval prior to its inclusion on IRIS. Consensus means that no member office isaware either of information that would conflict with the final carcinogenicity summary, or of analyses that would suggest that adifferent view is more credible. Such assurance rests on the capabilities ofthe individuals who represent their offices; thus, every effort is made to seek scientists who are both expert inthe area of human health assessment and who can represent their office.
Peer review has generally been part ofthe IRIS information development processes from the beginning ofthe system. Inthe preparation of summaries, emphasis has been placed on the use of peer-reviewed EPAassessments. These have included Office of Pesticide Programs assessments that have received both program office peer review and Science Advisory Panel review. Other EPA documentation includes assessments prepared by OHEA such as Health Assessment Documents, Health and Environmental Effects Documents, and Health Effects Assessments. These documents receive OHEA review and program office review and some receive Science Advisory Board (SAB) or other external review. Assessments developed by orfor the Office of Ground Water and Drinking Water and incorporated

7in either Drinking Water or Ambient Water Criteria Documents, or in Drinking Water

HealthAdvisories generally receive extensive Agency review and SAB review prior to discussion by CRAVE. On occasion, risk assessments that were contained indraft documents have been discussed by CRAVE. Inthese instances, results ofthe work group deliberations have been incorporated into the document development process atthe program office or program support office level. Loading ofthe information on IRIS is delayed pending completion ofthe document. Ifconsensus is not reached atthe meeting it isgenerally because an issue is raised that requires resolution. Work group deliberations continue until consensus is achieved. Inthe case of substance-specific issues, the substance is referred back to the member office that initiated the reviewfor more information and clarification. In some instances, it has been necessary for more than one program office to engage in adialogue to resolve the issue. For general issues, CRAVE practice has been to form asubcommittee to prepare an issue paper that is subsequently discussed at aspecial meeting. As examples ofthis process, issue papers have been developed for (1) issues relating to accuracy and precision of quantitative dose-response information, (2)factors involving confidence in quantitative estimates, and (3)use of split classifications and combining estimates. When consensus is not achieved on a particular substance at a meeting ofthe CRAVE, it isconsidered to have “under review” status. Ifafterthree months, there is nofurther activity to bring the substance back to the work group for additional review, the substance loses its “under review” status. The substance isthen dropped from the work group review list after notifying the responsible office. Any office may resubmit the substance for further discussion at any time. Reference Dose (RfD)/Reference Concentration (RfC): Information Development Procedures
The purpose ofthe RfD/RfC Work Group isto reach consensus on oral RfDsand inhalation RfCsfor noncancer chronic human health effects developed by or insupport of program offices and the regions. The work group also works to resolve inconsistent RfDsor RfCsamong program offices andto identify, discuss, and resolve generic issues associated with methods used to estimate RfDsand RfCs. Scientists are selected by executive appointment from respective member offices. Membership isopen to all major Agency program and regional offices. There aretwo work group co-chairs. Inaddition, scientists from the Agency for Toxic Substances and Disease Registry and the Food and Drug Administration are invited to work group meetings asobservers to assistthe Agency inthe information gathering process. Their

8involvement fosters better communication and coordination among federal agencies

regarding assessment approaches and data evaluation. Members reflect a variety of pertinent scientific disciplines including expertise in the fields of general and inhalation human toxicology. Member offices schedule substances for discussion through the work group cochairs for specific meetings, usually one or two months inadvance. Regional requests for specific substance discussions are routed through the co-chairs, who then either schedule these substances inthe usual manner or, ifthe region has not prepared afile, requests an appropriate office to undertake that task.
The RfD/RfC Work Group usually meets once amonth fortwo days. Substances are discussed at the request of any Agency office or region. The requesting office generally prepares afilethat consists ofasummary sheet, acopy ofthe critical study and supporting documentation, and distributes these to work group members prior to the meeting. Consensus generally means that no member office isaware either of information thatwould conflict with the RfDor RfC,orofanalyses thatwould suggest adifferent value that is more credible. Such assurance rests on the capabilities of the individuals who represent their offices; thus, alarge effort isconducted biannually to seek scientists who are both expert inthis area of assessment and can represent their offices. RfD or RfC summaries are not always based on existing EPA assessment documents but may be based on assessments prepared specifically forthe work group. This isafundamental difference between theusual processes ofthe RfD/RfC Work Group and those of CRAVE. As stated previously, the general rule has been that for a substance to be brought to the CRAVE Work Group for review there should be an existing peer-reviewed Agency health effects document. However, for RfDsthere may or may not be an existing EPAdocument on which to base work group deliberations and in the case of RfCs, there have not, to date, been any existing peer-reviewed EPA documents. Thus, RfC deliberations are based on extensive assessment summaries prepared expressly for the work group. Therefore, when an Agency peer-reviewed document isnotavailable, aswith RfCsandsome RfDs,extensiveassessment summaries are included on IRIS once the work group has completed verification and reached consensus. The work group co-chairs assurethatthefinal summary accurately expresses the consensus view of the group at the meeting as specified in the meeting notes. Once unanimous consensus is reached, the substance-specific summary for either an RfDor RfC is prepared for inclusion on IRIS. In some cases, the work group agrees that adequate information isnot availableto derive an RfDor RfC. A message isthen put on IRIS to that effect and the reasons for the “not verifiable” status. In most cases the message statesthatthe health effects datafor aspecific substance were reviewed bythe work group and determined to be inadequate for derivation of an RfDor RfC.

9Conflicts that arise during a meeting regarding a given RfDor RfCgenerally are

resolved outside the meeting byscientists from the appropriate offices, andthen brought back tothe work group for clarification and subsequent consensus. Conflicts that arise regarding the methods bywhich RfDsor RfCsareestimated, orthe incorporation of new methods, aregenerally taken upatseparately scheduled meetings ofthework group, for which the sponsoring office prepares the appropriate material for review. While, as discussed above, the RfD/RfC Work Group process is somewhat different from that of the CRAVE, they both use generally the same consensus procedures. Other procedural similarities are discussed inthe following paragraphs. Onoccasion, scientific issues on individual substances, methods, oron ageneral question cannot be resolved at the work group level. In the event that an issue is unresolvable inthe work group processes, the issue is referred to the RiskAssessment Council. In some cases, the issue is brought to the IRIS Oversight Subcommittee for review and discussion, prior to consideration bythe fullCouncil. Ifan issue is raised to the Council, it may be referred by the Council to the Risk Assessment Forum for consultation. Both the CRAVE and RfD/RfC Work Groups, through the IRIS Information Submission Desk, discussed in the companion FEDERAL REGISTER notice, have received comments and studies from interested parties outside ofthe Agency that were either pertinent to the work group’s initial review or resulted in reconsideration of a particular substance assessment. Further,thework groups often contact the authors of a primary study if clarifications are necessary, and consult with outside experts on scientific issuesthat require expertisethat isnot present inthework group. Also,through professional societies and other private sector organizations, the work groups have fostered discussions andexchanges regarding newandinnovative approaches to human health assessment methodologies.



### Methods and Guidelines
Both Agency work groups responsible for the development of the health hazard information on IRISuseAgency scientific methods documents and EPA’s riskassessment guidelines as the basis for their work. These guidelines and methodologies used to develop the RfDor RfChave been peer reviewed bythe SAB. Summaries of methods used for development of oral RfDs and carcinogenicity information on IRISarecontained inIRISbackground documents thatareavailable onthe system. A paper copy ofthe oral RfDand CRAVE background documents, “Reference Dose (RfD); Description and UseinHealth RiskAssessment” (Regulatory Toxicology and Pharmacology 8:471-486, 1988) and The U.S. EPAApproach for Assessing the Risks Associated with Chronic Exposures to Carcinogens, respectively, is also available from IRIS User Support by calling: (513)569-7254.
10The draft methods document, interim Methods for Development of Inhalation

Concentrations (EPA/600/8-90/066A), isthe basisforthe inhalation WCs. Acopy ofthe document isavailablefrom the Center for Environmental Research Information (CERI)by calling: (513) 569-7562. Please citethe EPAdocument number (EPA/600/8-90/066A) when requesting a copy. A revised RfC methodology document based on SAB peerreview comments will undergo asecond SAB review and will be available laterthis year. The CRAVE background document is based on EPA’s 1986 Guidelines for Carcinogen RiskAssessment (51FR33992-34003). Acopy ofthe EPArisk assessment guidelines (EPA/600/8-87/045) isalso available by calling CERI. 

### Public Involvement
The section inthe companion FEDERAL REGISTER notice (February 25, 1993, 58 FR 11490) on Current Opportunities for Public Involvement in the IRIS Process elaborates on opportunities for public input and dialogue.

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